Enhancing Solubility and Dissolution of Anti-Fungal Drugs: A Comparative Study of Solid Dispersion and Co-Crystallization

Fungal infections have emerged as a significant and escalating global health burden, particularly affecting immunocompromised populations such as patients with HIV/AIDS, cancer patients receiving chemotherapy, organ transplant recipients, and individuals suffering from chronic metabolic or inflammatory disorders. Both invasive and superficial mycoses are associated with high morbidity and mortality, and their incidence has increased markedly over the past few decades. This growing clinical concern is further exacerbated by the emergence of antifungal resistance, limited therapeutic options, and suboptimal drug exposure at target sites, thereby intensifying the need for effective and bioavailable antifungal therapies [1]. Despite notable progress in antifungal drug discovery and medicinal chemistry, formulation-related challenges continue to hinder optimal therapeutic performance. Many clinically important antifungal agents, including itraconazole, ketoconazole, posaconazole, voriconazole, and fluconazole, exhibit poor aqueous solubility and dissolution-limited absorption. According to the Biopharmaceutics Classification System (BCS), a majority of these compounds are categorized as class II or IV drugs, where low solubility and variable dissolution rates represent the primary barriers to oral bioavailability [2]. As a result, inconsistent plasma drug levels, high inter- and intra-patient variability, dose escalation, food-dependent absorption, and increased risk of adverse effects are frequently observed in clinical practice.

To overcome these limitations, numerous formulation strategies aimed at enhancing solubility and dissolution have been extensively investigated. Conventional approaches include particle size reduction, salt formation, lipid-based delivery systems, cyclodextrin inclusion complexes, nanosuspensions, and amorphous formulations (Table 1). While these techniques have demonstrated varying degrees of success, issues related to physical stability, scalability, cost, and regulatory complexity often limit their widespread application. In this context, solid dispersion and co-crystallization have gained increasing attention as robust and industrially feasible alternatives for solubility enhancement [3][4]. Solid dispersion systems improve drug dissolution primarily by reducing crystallinity, enhancing wettability, and increasing surface area, whereas co-crystallization modulates crystal lattice energy through supramolecular interactions without altering the chemical identity of the drug. Both approaches offer distinct mechanistic advantages and have shown promising results for poorly soluble antifungal agents.

This review aims to critically and systematically compare solid dispersion and co-crystallization techniques with respect to their underlying principles, formulation methodologies, performance in antifungal drug delivery, and recent research advancements reported between 2018 and 2025. The discussion is intended to guide formulation scientists in selecting rational and translational solubility enhancement strategies for next-generation antifungal therapeutics.

Table 1. Antifungal Drugs and Solubility Enhancement Approaches

2. Solubility and Dissolution Challenges of Antifungal Drugs

2.1 Physicochemical Characteristics

The physicochemical properties of antifungal drugs play a decisive role in determining their formulation feasibility and in vivo performance. A common challenge associated with most clinically used antifungal agents is their poor aqueous solubility, which directly compromises dissolution rate and oral bioavailability. This limitation primarily arises from their high lipophilicity, rigid molecular structures, and strong crystal lattice energy, which collectively hinder drug–solvent interactions in aqueous environments. Additionally, many antifungal drugs exhibit limited ionization at physiological pH, further restricting their solubility in gastrointestinal fluids.

Itraconazole represents a classic example of these challenges. It is a highly lipophilic triazole antifungal with an aqueous solubility reported to be less than 1 ng/mL, rendering conventional formulation approaches largely ineffective [5]. Its rigid crystalline structure and high melting point contribute to a strong lattice energy, making it resistant to dissolution even in the presence of solubilizing agents. As a result, itraconazole formulations often require advanced strategies such as solid dispersions, cyclodextrin inclusion complexes, or lipid-based delivery systems to achieve therapeutically relevant plasma concentrations.

Similarly, other azole antifungals such as posaconazole and ketoconazole demonstrate pronounced pH-dependent solubility. These drugs are weakly basic in nature and exhibit higher solubility under acidic conditions, while their solubility markedly decreases at neutral or alkaline pH. This pH-sensitive behavior leads to variable and unpredictable absorption, especially in patients with altered gastric pH due to food intake, disease conditions, or concomitant use of acid-suppressing agents. Consequently, fluctuations in gastrointestinal pH can significantly influence drug dissolution, absorption, and ultimately clinical efficacy.

Overall, the unfavorable physicochemical characteristics of antifungal drugs present a substantial barrier to effective drug delivery. A thorough understanding of these properties is therefore essential for rational formulation design and for the development of innovative strategies aimed at enhancing solubility, dissolution, and bioavailability.

2.2 Clinical Implications

Poor aqueous solubility and slow dissolution rate are critical limitations that significantly compromise the clinical performance of many drugs, particularly those belonging to Biopharmaceutics Classification System (BCS) class II and IV. Inadequate solubility often translates into reduced oral bioavailability, as only the dissolved fraction of a drug is available for absorption across the gastrointestinal epithelium. This limitation can result in a delayed onset of therapeutic action, which is especially problematic in the management of acute or severe infections.

To compensate for poor absorption, higher drug doses are frequently required, increasing formulation complexity and treatment costs. More importantly, dose escalation elevates the risk of dose-related adverse effects and systemic toxicity, thereby narrowing the therapeutic window. Inconsistent or insufficient drug exposure at the target site may also lead to subtherapeutic plasma concentrations, contributing to therapeutic failure. In the context of antimicrobial therapy, such variability can promote the development of drug resistance, posing a serious public health concern.

Therefore, improving drug solubility and dissolution is essential not only to enhance pharmacokinetic profiles but also to ensure consistent therapeutic efficacy and long-term clinical reliability [6].

3. Solid Dispersion Technique

3.1 Concept and Mechanism

The solid dispersion technique is one of the most widely explored and effective strategies for improving the solubility and dissolution behavior of poorly water-soluble drugs. In this approach, one or more active pharmaceutical ingredients are dispersed within an inert, hydrophilic carrier matrix in the solid state. Depending on the formulation method and carrier used, the drug may be present as finely divided crystalline particles, partially or completely amorphous material, or as molecularly dispersed entities within the polymeric matrix [7]. This structural modification fundamentally alters the physicochemical environment of the drug, leading to enhanced dissolution performance.

The primary mechanism underlying solubility enhancement in solid dispersions is the reduction or complete elimination of drug crystallinity. Amorphous drugs possess higher free energy compared to their crystalline counterparts, resulting in greater apparent solubility and faster dissolution rates. Additionally, the intimate mixing of the drug with a hydrophilic carrier leads to a marked increase in effective surface area upon contact with dissolution media. This fine dispersion minimizes drug particle aggregation and promotes rapid drug release.

Improved wettability is another key contributor to enhanced dissolution. Hydrophilic polymers such as polyethylene glycol, polyvinylpyrrolidone, and hydroxypropyl methylcellulose readily interact with aqueous media, facilitating penetration of the dissolution medium into the drug matrix. This improves the interfacial contact between the drug and the solvent, thereby accelerating dissolution. In some systems, specific drug–polymer interactions, such as hydrogen bonding, further stabilize the amorphous state and prevent recrystallization during storage.

Overall, solid dispersion technology offers a versatile and scientifically robust platform for addressing solubility-related challenges. By modifying drug crystallinity, increasing surface area, and enhancing wettability, this technique enables significant improvements in dissolution behavior, making it particularly valuable for the formulation of poorly soluble drugs with otherwise limited bioavailability [8].

3.2 Types of Solid Dispersions

Solid dispersions are broadly classified into different generations based on the nature of the carrier used and the resulting physicochemical behavior of the system. This classification reflects the progressive evolution of the technique aimed at overcoming limitations related to solubility, stability, and drug release performance.

First-generation solid dispersions employ crystalline carriers such as urea, sugars, or organic acids. In these systems, the drug is dispersed within a crystalline matrix, which can reduce particle size and improve dissolution to some extent. However, the presence of a crystalline carrier often limits the achievable solubility enhancement. Moreover, phase separation and limited molecular-level dispersion may occur, resulting in modest improvements and potential reproducibility issues. Due to these constraints, first-generation systems are now considered less favorable for modern pharmaceutical applications [9].

Second-generation solid dispersions introduced amorphous polymeric carriers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), and hydroxypropyl methylcellulose (HPMC). These carriers enable the drug to exist in an amorphous or molecularly dispersed state, significantly enhancing solubility and dissolution rates. The polymers also improve wettability and may form specific interactions with the drug, helping to stabilize the amorphous form. Despite these advantages, second-generation dispersions can still suffer from physical instability, particularly recrystallization of the drug during long-term storage or under stress conditions.

To address these challenges, third-generation solid dispersions incorporate surface-active agents or surfactant-based carriers such as poloxamers, Soluplus®, and Gelucire®. These systems combine the benefits of polymeric matrices with the solubilizing and wetting properties of surfactants. The presence of surfactants not only enhances dissolution but also improves physical stability by inhibiting drug recrystallization and promoting consistent drug release. As a result, third-generation solid dispersions demonstrate superior dissolution performance and storage stability. Recent studies increasingly favor third-generation solid dispersions, as they offer a balanced approach to solubility enhancement and formulation robustness, making them highly promising for the development of poorly water-soluble drugs [10].

3.3 Preparation Methods

The performance of a solid dispersion system is strongly influenced by the method used for its preparation, as the processing technique determines drug distribution, physical state, and long-term stability. Several preparation methods have been developed to suit different drug–carrier combinations, each with distinct advantages and limitations. Hot-melt extrusion (HME) is one of the most widely adopted techniques for preparing solid dispersions. In this method, the drug and carrier are blended and heated above their glass transition or melting temperature, followed by extrusion through a die to form a homogeneous solid matrix. The intense mixing and thermal energy facilitate molecular-level dispersion of the drug within the polymer. HME is a solvent-free, continuous process that offers excellent scalability and reproducibility, making it highly attractive for industrial manufacturing. Furthermore, its growing regulatory acceptance and compatibility with downstream processing such as pelletization or tablet compression have positioned HME as a preferred method for commercial formulations [11]. However, its application may be limited for thermolabile drugs.

Solvent evaporation is a conventional and widely used laboratory-scale technique. In this approach, both the drug and carrier are dissolved in a common volatile solvent or solvent mixture, followed by solvent removal under reduced pressure or controlled heating. As the solvent evaporates, the drug becomes uniformly dispersed within the polymeric matrix, often in an amorphous form. This method is simple and suitable for heat-sensitive drugs; however, residual solvent issues, environmental concerns, and limited scalability restrict its industrial applicability.

Spray drying is an advanced solvent-based technique that involves atomization of a drug polymer solution into fine droplets, which are rapidly dried using hot air. The rapid solvent evaporation promotes the formation of amorphous, porous particles with high surface area, leading to enhanced dissolution rates. Spray drying allows precise control over particle size and morphology and is easily scalable. Nevertheless, the use of organic solvents and the risk of drug recrystallization during storage remain important considerations.

Freeze drying (lyophilization) involves freezing the drug–carrier solution followed by sublimation of the solvent under vacuum. This method produces highly porous, low-density solid dispersions with excellent dissolution characteristics. Freeze drying is particularly useful for thermally unstable drugs and sensitive biomolecules. However, the process is time-consuming, energy-intensive, and costly, limiting its use primarily to specialized applications [10][12].

In summary, the choice of preparation method depends on drug properties, carrier selection, scalability requirements, and regulatory considerations. Among these, hot-melt extrusion has emerged as a robust and industry-friendly technique, offering a sustainable and efficient platform for solid dispersion development.

3.4 Application to Antifungal Drugs

Solid dispersion technology has been extensively applied to overcome the solubility and bioavailability challenges associated with antifungal drugs. Due to their high lipophilicity and strong crystalline nature, many antifungal agents exhibit poor aqueous solubility, leading to variable therapeutic outcomes. Incorporation of these drugs into solid dispersion systems has consistently demonstrated significant improvements in dissolution behavior and in vivo performance. Itraconazole, a classic example of a poorly soluble antifungal drug, has shown remarkable enhancement when formulated as solid dispersions with hydrophilic carriers such as polyethylene glycol (PEG). Studies have reported nearly a ten-fold increase in dissolution rate compared to the crystalline drug, resulting in improved drug availability for absorption [13]. Similarly, posaconazole, which exhibits pH-dependent solubility and erratic absorption, has been successfully formulated into amorphous solid dispersions using hydroxypropyl methylcellulose (HPMC). These systems not only enhanced dissolution but also significantly improved oral bioavailability, leading to more consistent plasma drug levels.

Even relatively water-soluble antifungals such as fluconazole have benefited from solid dispersion approaches. Rapid drug release from polymeric matrices has been shown to enhance antifungal activity, particularly by achieving faster and more effective drug concentrations at the site of action [14].

Collectively, these findings highlight the versatility of solid dispersion systems in improving the therapeutic performance of antifungal drugs by enhancing solubility, dissolution, and pharmacological efficacy.

3.5 Advantages and Limitations

3.5.1 Advantages

1. Significant solubility enhancement: Solid dispersion systems effectively convert poorly soluble drugs into amorphous or molecularly dispersed forms, resulting in a marked increase in apparent solubility and dissolution rate compared to crystalline drugs.
2. Improved bioavailability: Faster dissolution and better wettability enhance drug absorption across the gastrointestinal tract, leading to improved and more consistent oral bioavailability.
3. Rapid onset of action: Enhanced dissolution enables quicker availability of the drug at the absorption site, which is particularly beneficial for drugs requiring prompt therapeutic effect.
4. Versatility of carriers: A wide range of hydrophilic polymers and surfactants can be employed, allowing flexibility in formulation design.
5. Well-established technology: Solid dispersion is a scientifically validated and widely studied approach, with increasing regulatory acceptance and successful commercial products.

3.5.2 Limitations

1. Physical instability: The amorphous state of drugs in solid dispersions is thermodynamically unstable and may undergo recrystallization during storage, potentially reducing solubility and dissolution over time.
2. Moisture sensitivity: Many polymeric carriers are hygroscopic, and exposure to moisture can accelerate drug recrystallization and compromise product stability.
3. Scale-up challenges: Solvent-based preparation methods often face difficulties during large-scale manufacturing due to residual solvent concerns, environmental issues, and process complexity.
4. Thermal constraints: Techniques such as hot-melt extrusion may not be suitable for thermolabile drugs.4. Co-Crystallization Technique

4. Co-crystallization technique

4.1 Concept and Fundamentals

Pharmaceutical co-crystallization has emerged as a promising crystal engineering approach to modify the physicochemical properties of active pharmaceutical ingredients (APIs) without altering their molecular structure. Co-crystals are defined as single crystalline phases composed of an API and one or more low-molecular-weight compounds, known as co-formers, in a fixed stoichiometric ratio. These components are held together through non-covalent interactions such as hydrogen bonding, π–π stacking, and van der Waals forces, resulting in a unique and well-ordered crystal lattice [15]. Unlike salt formation, co-crystallization does not require the presence of ionizable functional groups or proton transfer between components. This makes the technique particularly attractive for neutral or weakly ionizable drugs that are unsuitable for salt formation. By carefully selecting pharmaceutically acceptable co-formers, such as organic acids, amides, or amino acids, it is possible to design co-crystals with tailored properties while maintaining the pharmacological identity of the drug.

From a mechanistic perspective, co-crystallization alters the crystal packing and intermolecular interactions within the solid state. This structural rearrangement can reduce lattice energy, improve crystal habit, and enhance interactions with solvent molecules, ultimately leading to improved solubility and dissolution behavior. In addition to solubility enhancement, co-crystals have been shown to improve other critical attributes, including stability, mechanical properties, and compressibility, which are important for downstream processing.

Importantly, co-crystals are considered distinct solid forms of an API and are recognized by regulatory agencies as viable pharmaceutical entities, provided the co-former is safe and well characterized. As a result, co-crystallization offers a rational and versatile strategy for optimizing drug performance without the need for chemical modification. Overall, the concept of pharmaceutical co-crystals bridges solid-state chemistry and drug formulation science, offering a powerful platform to address solubility-related challenges while preserving the therapeutic integrity of the active molecule [16].

4.2 Co-formers and Selection Criteria

The choice of an appropriate co-former is a critical step in the successful design of pharmaceutical co-crystals, as it directly influences crystal formation, stability, and performance. Commonly used co-formers include organic acids such as succinic acid and fumaric acid, which readily participate in hydrogen bonding with drug molecules. Amides like nicotinamide are also widely employed due to their strong hydrogen bond donor–acceptor capabilities and excellent pharmaceutical acceptability. In recent years, increasing attention has been given to polyphenols and other Generally Recognized as Safe (GRAS) compounds, as they offer both functional and regulatory advantages.

Co-former selection is primarily guided by hydrogen bond donor–acceptor complementarity between the active pharmaceutical ingredient and the co-former, ensuring the formation of a stable and predictable supramolecular synthon. Equally important considerations include the safety profile, regulatory acceptance, and physicochemical compatibility of the co-former. A rational and systematic selection strategy enhances the likelihood of forming pharmaceutically viable co-crystals with improved solubility and performance.

4.3 Preparation Techniques

The successful formation of pharmaceutical co-crystals largely depends on the preparation technique employed, as each method influences crystal purity, yield, and solid-state properties. Several techniques have been developed to facilitate efficient co-crystal formation under different experimental and industrial conditions.

Solvent evaporation is one of the most commonly used methods for co-crystal preparation. In this approach, the active pharmaceutical ingredient and co-former are dissolved in a suitable solvent or solvent mixture, followed by controlled evaporation. As the solvent gradually evaporates, supersaturation occurs, promoting co-crystal nucleation and growth. This method is simple and effective for screening studies; however, it may suffer from solvent selection challenges and limited scalability.

Neat grinding involves the mechanical mixing of the drug and co-former without the use of any solvent. The mechanical energy supplied during grinding induces molecular contact and facilitates co-crystal formation. While environmentally friendly, neat grinding may result in incomplete conversion. To overcome this, liquid-assisted grinding (LAG) introduces a small amount of solvent to enhance molecular mobility without fully dissolving the components. LAG is widely favored due to its simplicity, high reproducibility, minimal solvent requirement, and ability to produce pure co-crystals efficiently [17].

Slurry conversion involves suspending the drug and co-former in a solvent in which one or both components have limited solubility. Over time, the system reaches thermodynamic equilibrium, leading to the transformation of the solid phases into a stable co-crystal form. This method is particularly useful for preparing thermodynamically stable co-crystals.

Supercritical fluid methods, typically using supercritical carbon dioxide, offer a solvent-free or low-solvent alternative for co-crystal formation. These techniques provide excellent control over particle size and morphology but require specialized equipment and higher operational costs.

Among these methods, liquid-assisted grinding stands out as a practical and reproducible approach for both laboratory-scale development and solid-state screening.

4.4 Co-Crystallization of Antifungal Drugs

Co-crystallization has gained increasing attention as an effective strategy for improving the pharmaceutical performance of antifungal drugs, many of which suffer from poor solubility and unfavorable solid-state properties. By altering crystal packing without modifying the chemical structure of the drug, co-crystals offer a rational approach to enhance dissolution, stability, and processability.

Itraconazole, a highly lipophilic antifungal agent, has been successfully co-crystallized with succinic acid, resulting in a marked improvement in dissolution rate and solid-state stability compared to the parent crystalline form [4][17]. The modified crystal lattice facilitates better interaction with dissolution media, thereby enhancing drug availability. Similarly, ketoconazole–nicotinamide co-crystals have demonstrated nearly a six-fold increase in solubility, attributed to improved hydrogen bonding interactions and reduced lattice energy [5][18]. These improvements translate into more predictable and efficient drug release profiles.

Voriconazole, another clinically important antifungal, has also shown significant benefits from co-crystallization. Reported co-crystals exhibited improved compressibility and dissolution behavior, which are advantageous for tablet formulation and large-scale manufacturing [6][18].

Overall, these studies highlight the potential of co-crystallization as a versatile and robust solid-state modification technique for antifungal drugs, offering simultaneous improvements in solubility, stability, and manufacturability.

4.5 Advantages and Limitations

4.5.1 Advantages [19]

1. Improves drug solubility without converting the API into an amorphous form
2. Maintains a stable crystalline structure, leading to better physical stability
3. Reduces the risk of recrystallization during storage
4. Allows tuning of physicochemical properties such as solubility, melting point, and dissolution rate
5. Preserves the chemical integrity and pharmacological activity of the drug
6. Suitable for drugs that are not amenable to salt formation

4.5.2 Limitations [20]

1. Requires extensive and systematic screening to identify suitable co-formers
2. Limited compatibility with pharmaceutically acceptable co-formers
3. Co-crystal formation is not guaranteed for all drug–co-former combinations
4. Regulatory classification and approval pathways may be complex
5. Additional solid-state characterization is necessary to confirm co-crystal formation
6. Scale-up and reproducibility can be challenging in some cases

5. Comparative Evaluation: Solid Dispersion vs Co-Crystallization

Solid dispersion and co-crystallization are two well-established solid-state strategies aimed at improving the solubility and performance of poorly water-soluble drugs, yet they differ fundamentally in their mechanisms and practical implications. Solid dispersions enhance solubility primarily by converting the drug into an amorphous or molecularly dispersed state within a hydrophilic carrier, leading to rapid dissolution and improved bioavailability (Table 2). However, the amorphous nature of these systems often raises concerns regarding physical stability and recrystallization during storage [20][21].

Table 2. Comparative Evaluation: Solid Dispersion vs Co-Crystallization

Figure 1: Comparative illustration of solid dispersion and co-crystallization strategies for enhancing the solubility and dissolution of antifungal drugs. (Figure created with BioRender.com, 2026.)